The Program Project grant application entitled "Mechanisms of PMN-Mediated Lung Inflammation and Injury" addresses the critical signaling pathways mediating neutrophil activation and endothelial activation, and the interactions between endothelial cells and neutrophils that mediate pulmonary vascular injury and edema. We will use multi-disciplinary strategies and involve investigators from Departments of Pharmacology, Microbiology and Immunology, and Medicine. Project 1 addresses the mechanisms of NADPH oxidase activation in endothelial cells and the generation of signals that induce NF-kb activation and ICAM-1 expression. Project 2 addresses the signaling mechanisms underlying the chemoattractant (fMet- Leu-Phe)-induced activation of NADPH oxidase in neutrophils. Project 3 addresses mechanisms of thrombin-induced activation of Ca 2+ signaling in endothelial cells in mediating NF-kB activation and ICAM- 1 expression, and the resulting neutrophil-mediated lung vascular injury. Project 4 addresses the role of cross-talk between neutrophils and endothelial cells via NADPH oxidase-derived oxidants in neutrophils in the mechanism of lung vascular injury. All projects will be supported by 3 cores: Administrative Core (Core A), Cell Culture and Vector Core (Core B), and Physiology and Imaging Core (Core C) which will integrate the aims of each project with the program's overall objective. The goal of the program is to address signaling mechanisms in neutrophils and endothelial cells that promote neutrophil endothelial interactions and induce the acute lung inflammatory injury. With a better understanding of the signaling pathways derived from endothelial-neutrophil co-culture experiments and mouse models, we hope to develop advanced therapeutic strategies that would be beneficial in preventing or reversing acute lung injury.